Intracavernous Administration of Adipose Stem Cells: A

MOJ Cell Science & Report
Intracavernous Administration of Adipose Stem Cells:
A New Technique of Treating Erectile Dysfunction in
Diabetic Patient, Preliminary Report of 6 Cases
Research Article
Abstract
Objectives: After revolutionized treatment of erectile dysfunction (ED) with
phosphodiesterase-5 inhibitors (PDE5) inhibitors, approximately 30% of
patients are non-responsive. An important cause of this is vascular and smooth
muscle dysfunction, as well as nerve atrophy. Stem cells are characterized by
anti-inflammatory activities, as well as possibility of differentiating into tissue
relevant to the penile architecture, and stimulation of angiogenesis. We report
the effects of intracavernosal application of adipose derived stem cells (ASC) on
diabetic erectile dysfunction.
Materials and Methods: Six type 2 diabetics who had failed to achieve an
erection for at least 6 months despite medications, and who are currently
awaiting penile prostheses, participated in this study. All laboratory results
were normal, except for erectile dysfunction and diabetes mellitus. A total of
1.5 x 10(7) adipose stem cells was infused into the corpus cavernosum. No
immunosuppressive measures were taken in any of the patients. International
index of erectile function-5, Encounter Profile Question 3 (SEP3), erection diary,
blood glucose diary, and medication dosage were followed for 6 months.
Volume 2 Issue 1 - 2015
Garber MG* and Carlos ND
Department regenerative medicine, Clinica Medica Quirurgica
Quantum, Spain
*Corresponding author: Garber Miguel Guillermo,
Department regenerative medicine, Clinica Medica
Quirurgica Quantum, Clara del Rey 31-33, Madrid, 28002,
Spain, Tel: 628766753; Email:
Received: June 18, 2014 | Published: March 02, 2015
Results: The mean age was 63.7 years (range, 55-81 years). Morning erections
were recovered in 4 participants within 2 month, and for all except 1 by the 95
days, and maintained for more than 4 months. Rigidity increased as the result of
stem cell therapy alone, but was insufficient for penetration. With the addition
of PDE5 inhibitor before coitus, 3 achieved penetration and experienced
orgasm, and maintained for more than 6 months. All but 1 reported increased
desire. During follow-up, 1 returned for prosthesis, 1 returned to a nonerectile
condition at 7 months, and 4 maintained erection sufficient for coitus with
medication until the 9th month. Blood glucose levels decreased by 2 weeks,
and medication dosages were reduced in all. Glycosylated hemoglobin levels
improved after treatment.
Conclusion: Human adipose stem cell therapy has positive effects on erectile
dysfunction in diabetes mellitus patients. Stem cells mediate mechanism may
contribute to these positive effects.
Keywords: Stem cell treatment; Erectly dysfunction; PDE5 inhibitors; Diabetes;
Adipose stem cell therapy; Regenerative medicine
Abbreviations: NO: Nitric Oxide; NANC: Non Adrenergic
Non Cholinergic; ED: Erectile Dysfunction; PDEIs:
Phosphodiesterase-5 Inhibitors; ASC: Adipose Stem Cells; IIEF:
International Index of Erectile Function; SC: Stem Cells; MSC:
Mesenchymal Stem cells; T2D: Type 2 Diabetes; IRS 1: Insulin
Receptor Substrate 1
Introduction
The hemodynamic phenomena of erection are regulated
by penile smooth muscle tone (arterial and trabecular). This
response requires a coordinated process, increases in arterial
inflow, originates from the pudenda arteries, relaxation of the
corporal smooth muscle, and inhibition of venous outflow
[1,2]. Key to this response is production of nitric oxide (NO)
from endothelial cells and non adrenergic non cholinergic
(NANC) postganglionic parasympathetic neurons, as well
as responsiveness to this [3]. The current treatments for
erectile dysfunction(ED) include psychotherapy, oral or
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injected medication, and penile prosthesis. Oral treatment
with phosphodiesterase-5 inhibitors (PDE5Is) as a first-line
monotherapy [4], but, a significant proportion of patients with
complex ED [5] are non-responsive (approximately 30% of
patients) [6]. An important cause of this is vascular and smooth
muscle dysfunction, [7] as well as nerve atrophy.
In diabetes, the activities of vasoconstrictors such as
Angiotensin II, endothelin-1 [8], and vascular endothelial
growth factor are increased [7]. The chronic complications of
diabetes mellitus affect multiple organs and cause microvascular
and macro vascular complications, in addition to nonvascular
complications. Erectile dysfunction is the second most-common
symptom of diabetes mellitus, [9] and affects 32% of men with
type 1 diabetes and 46% of men with type 2 diabetes [6]. Erectile
dysfunction is caused by the impaired relaxation of corporal
smooth muscle cells [10]. This condition is thought to be induced
by a combination of disorders in the central or peripheral nervous
MOJ Cell Sci Rep 2015, 2(1): 00018
Intracavernous Administration of Adipose Stem Cells: A New Technique of Treating
Erectile Dysfunction in Diabetic Patient, Preliminary Report of 6 Cases
system, hormone production, vascular integrity, or endothelial
smooth muscle, as well as psychological and other factors
[11,12]. Stem cells hold great promise for regeneration because
of their ability to self-renewal, potentiality for differentiation, and
homing or migration, depending on the stimuli received. Some
types of adult stem cells, which exist within matured organs,
are now clinically available, and their therapeutic effects have
been firmly established. Adult stem cells may prove invaluable
in the development of new therapeutic applications for a variety
of incurable or difficult-to-cure diseases [13-18]. The adiposetissue-derived stem cells (ASC) are similar to bone marrow stem
cell in the ability to differentiate, provide therapeutic benefit, and
the easy and safety of cell harvest. Adipose tissue is a potential
source of stem cells for treatment of erectile dysfunction, which
highlights the possibility of an effective clinical therapy [19-21].
Stem cells are characterized by multipotent differentiation, and
stimulation of angiogenesis/regeneration. We report the effects
of intracavernosal application of adipose stem cells (ASC) on
diabetic erectile dysfunction patients.
Materials and Methods
Characteristics of participants
Six diabetics type 2 patients who had failed to achieve
an erection for at least 6 months despite medications, (oral
phosphodiesterase 5 inhibitor, (PDE5 inhibitor), or prostaglandin
E 1, (PGE1) injection), for a mean of 63.7 years (range, 55-81
years), and who are currently awaiting penile prostheses,
participated in this study. This study, which confirms the ethical
guidelines of the 1975 Helsinki Declaration, was conducted as
a master protocol study and all participants were informed of
the materials (stem cells) and the nature of treatments to be
used; additionally, written informed consent was obtained from
all of the subjects. International index of erectile function-5 and
sexual encounter profile questionnaires, and standard erectile
dysfunction evaluations, including medical history, thorough
physical examination, testosterone and prolactin levels, and
penile duplex Doppler ultrasonography were performed for all
patients.
Among many candidates, only those individuals with a body
mass index between 19 and 23 were included in this study. To
exclude patients that might have diseases, other than diabetes
mellitus and erectile dysfunction, all participants were subjected
to ancillary tests, including blood and serologic studies (CBC,
serologic series 12 including lipids, tumor markers <AFP,
CEA, CA19-9, PSA>, VDRL, AIDS, hepatitis Ag/Ab, H. pylori,
electrolytes, C-reactive protein, ASO titer, ESR, RA factor) tests,
urine studies (urine analysis, microscopic examination), imaging
studies (ultrasound examinations for thyroid, heart, liver,
kidney, and prostate; and computed tomography scans for brain,
chest, and abdomen), electrocardiogram, and funduscopy. All
participants had only diabetes mellitus and erectile dysfunction
but were within normal range for testosterone and prolactin
(testosterone levels were examined every visit during followup). Anybody with an abnormal finding on these ancillary studies
was excluded from this study. No immunosuppressive measures
were applied. International index of erectile function-5 and
blood glucose were monitored for 6 to 12 months. The patients’
hormonal levels were checked every visit.
Copyright:
©2015 Garber et al.
2/4
Characteristics of adipose stem cells
Human adipose tissues were obtained by simple liposuction
from the abdominal subcutaneous fats with an informed
consent. Subcutaneous adipose tissues were digested with
collagenase I (1 mg/mL) for the enzymatic digestion of adipose
tissue with collagenase type IA and the isolation of the SVF via
centrifugation. Plating of the SVF results in eventual selection
and expansion of the Adult Stem Cells (ASCs) population. They
yield reached around 1 × 10(6) ASCs per gram adipose tissue,
and CD29, CD34, CD44, CD45 and CD105 were detected by flow
cytometry. The detection rates of CD29, CD44, CD105, CD34 and
CD45 were 98.89%, 93.73%, 86.99%, 0.19% and 0.16%.The
1.8 x 10(7). The stem cells were infused into the both corpus
cavernosum of each patient. The penile root was clamped
with a band before injection and released 30 minutes after the
adipose stem cells were injected to prolong the transplanted cell
residence time, and increase the graft.
Follow-up
All participants submitted an international index of erectile
function questionnaire (Table 1) at every visit, before a followup interview. The international index of erectile function (IIEF)
questionary addresses the relevant domains of male sexual
function (that is, erectile function, orgasmic function, sexual
desire, intercourse satisfaction, and overall satisfaction), is
psychometrically and has been linguistically validated in 10
languages. The IIEF demonstrates the sensitivity and specificity
for detecting treatment-related changes in patients with erectile
dysfunction. Dosages of a hypoglycemic agent or insulin declined
during periods in which the blood glucose level dropped below
5.55 mmol/L (100 mg/mL). All patients were instructed to
use the PDE5 inhibitor when they wished to engage in sexual
intercourse after the stem cell therapy. All patients monitored
their fasting blood sugar at home every day, and monthly at the
hospital, and their glycosylated hemoglobin levels also were
checked monthly at the hospital. Participants were encouraged
to reduce their medication dosage when the fasting blood sugar
fell below 5.55 mmol/L (100 mg/mL) to prevent hypoglycemia.
For each patient, an erection diary, blood glucose diary, and
medication dosage were recorded daily, and the patients were
followed for 12 months.
Results
The 6 participants ages ranged from 59.4 years (range, 55-72
years). Penile duplex Doppler ultrasonography was conducted
for all 6 participants before stem cell therapy, and these records
demonstrated that all had reduced peak systolic velocities in
both cavernosal arteries-less than 22 cm/sec. All participants
exhibited some inconsistent changes in testosterone levels on
their follow-ups, but these variations were within normal limits.
Additionally, some changes in international index of erectile
function-5 scores were noted. Among the 6 experimental
participants who, before treatment, had no erections in the
morning or during sexual activity, 4 experienced morning
erections by 1 month after treatment, and the second month
all but 1 regained morning erections (question 1); this was
maintained for 12 month. Six of the experimental participants
experienced increases in penile hardness with time from stem
cell therapy only; however, the degree of increased hardness was
Citation: Garber MG and Carlos ND (2015) Intracavernous Administration of Adipose Stem Cells: A New Technique of Treating Erectile Dysfunction
in Diabetic Patient, Preliminary Report of 6 Cases. MOJ Cell Sci Rep 2(1): 00018. DOI: 10.15406/mojcsr.2015.02.00018
Copyright:
©2015 Garber et al.
Intracavernous Administration of Adipose Stem Cells: A New Technique of Treating
Erectile Dysfunction in Diabetic Patient, Preliminary Report of 6 Cases
still insufficient for effective penetration in one patient. With the
addition of a PDE5 inhibitor (sildenafil citrate 100 mg), 5 could
achieve penetration, maintenance, and orgasm, and retained that
ability (questions 3 and 4) at the sixth month after treatment. At
12 months’ follow-up, case 2 reported not being able to maintain
penetration, even when using the PDE5 inhibitor. All expressed
desire before and after cell therapy, and all but 1 participant
reported an increased desire in both frequency and intensity
after stem cell treatment. Hormonal levels exhibited individual
and intrapersonal variations at each test, but again, all remained
within normal range. During 12 months follow-up, 1 participant
3/4
turned for prosthesis, 1 could achieve only poor erections at 10
months, and 4 patients maintained erection sufficient for coitus
with the help of medication. Three of the patients who could
achieve penetration and maintenance also experienced orgasm.
With regard to the effects of stem cells on erectile dysfunction,
(4/6) of the subjects agreed that stem cell therapy applied alone
had some effect on erectile dysfunction, although this effect was
insufficient (question 13), and 5 (5/6) of the subjects regarded
stem cell therapy as effective for erectile dysfunction when
combined with a PDE 5 inhibitor.
Over the past 6 months
1
2
3
4
5
How do you rate your
confidence that you could
get and keep an erection
When you had erections
with sexual stimulation,
how often were your
erections hard enough for
penetration?
During sexual intercourse,
how often were you able
to maintain your erection
after you had penetrated
your partner?
During sexual intercourse,
how difficult was it to
maintain your erection to
completion of intercourse?
When you attempted sexual
intercourse, how often was
it satisfactory for you?
Table 1: The IIEF-5 Questionnaire (SHIM).
Very low
Low
Moderate
High
Very high
Almost never or
never
A few times
Sometimes
Most times
Almost always or
always
1
2
3
4
(Much less than
half the time)
2
About half the
time
3
Much more than
half the time
4
1
(Much less than
half the time)
2
(About half the
time)
3
(Much more than
half the time)
4
1
2
3
4
1
Almost never or
never
Extremely difficult
Almost never or
never
1
A few times
Very difficult
A few times
(Much less than
half the time)
2
Please encircle the response that best describes you for the following five questions.
Total Score:
Sometimes
Difficult
Sometimes
(About half the
time)
3
Most times
5
5
Almost always or
always
5
Slightly difficult
Not difficult
Most times
Almost always or
always
(Much more than
half the time)
4
5
5
1-7: Severe ED; 8-11: Moderate ED; 12-16: Mild-moderate ED; 17-21: Mild ED; 22-25: No ED
Subjects blood glucose levels began to drop from 2 weeks
after treatment, and 5 of 6 evidenced some reduction in fasting
blood sugar by 3 month. The insulin dosage had to be dropped
at 1 month in 2 cases owing to lower fasting blood sugar
(lower than 5.55 mmol/L (100 mg/mL); and at 4 months, a
hypoglycemic agent had to be reduced to maintain blood glucose
levels at above 5.5 mmol/L (100 mg/mL). The most elderly of
the subjects (No. 6) evidenced no changes in blood glucose levels
after stem cell therapy. Glycosylatedhemoglobin’s improved
beginning in the third month after treatment in all patients.
The lowered blood glucose levels in each patient. There were
no adverse effects after stem cell therapy, even without immune
suppression. Overall, only 1 patient reported confidence in the
effects of stem cell therapy on erectile dysfunction without a
PDE5 inhibitor.
Discussion
Stem Cells (SC) therapy for chronic disease has been
investigated in several preclinical studies and clinical trials,
Adipose Stem Cell (ASC) is the most commonly employed SC,
likely due to its ease of isolation from an abundant tissue source.
The rationale for adipose derivates stem cell therapy of patients
with erectile dysfunction is strong set that:
i. The penile vasculature is the most endothelial-rich
anatomical region of the body, thus even a small amount of
therapeutic cells are likely to be incorporated
ii. Blood flow in the flaccid penis is slower compared to
systemic circulation, thus allowing for superior retention
iii. Ease of injection given its external location.
From an ethical perspective, the procedure of penile
prosthesis implantation requires destruction of the cavernous,
thus making it irreversible. The reduction in fasting blood glucose
can be explained investigative trials show (Mesenchymal Stem
cells (MSC) infusion ameliorated hyperglycemia in rats with
type 2 diabetes (T2D). Infusion of MSCs during the early phase
promoted β-cell function, also ameliorated insulin resistance,
Citation: Garber MG and Carlos ND (2015) Intracavernous Administration of Adipose Stem Cells: A New Technique of Treating Erectile Dysfunction
in Diabetic Patient, Preliminary Report of 6 Cases. MOJ Cell Sci Rep 2(1): 00018. DOI: 10.15406/mojcsr.2015.02.00018
Intracavernous Administration of Adipose Stem Cells: A New Technique of Treating
Erectile Dysfunction in Diabetic Patient, Preliminary Report of 6 Cases
Copyright:
©2015 Garber et al.
4/4
whereas infusion in the late phase merely ameliorated insulin
resistance. Infusion of MSCs resulted in an increase of GLUT4
expression and an elevation of phosphorylated insulin receptor
substrate 1 (IRS-1) and Akt (protein kinase B) in insulin
target tissues. These data indicate that multiple roles and
mechanisms are involved in the efficacy of MSCs in ameliorating
hyperglycemia in T2D [22].
8. Tousoulis D, Tsarpalis K, Cokkinos D, Stefanadis C (2008) Effects
of insulin resistance on endothelial function: possible mechanisms
and clinical implications. Diabetes Obes Metab 10(10): 834-842.
Even though in the study we performed, the sample is
rather small; we can infer that the use of Adipose derived
stem cell therapy has positive effects on erectile dysfunction in
diabetes mellitus patients. Taking into consideration this type
of population, bombarded all day with “magic potions” as well
as they reticence regarding surgical option, the practicability
of the injection procedure, the fact that no adverse effects
were observed, and the simplicity of the procedure, supports
expanded clinical trials using this kind of intervention may be
added to the already vast armamentarium in the treatment of
ED. Maybe using this therapy prophylactically, implementing
early in the treatment of patient with DM, before the onset of ED
symptoms, may prevent or delay the early onset of the one most
distressing side effect of this debilitating disease that, Diabetes
Mellitus truly is, the feasibility of the injection procedure, the fact
that no adverse effects were noted, and the ease of the procedure,
supports expanded clinical trials using this intervention will be
needed.
11. Dunsmuir WP, Holmes SA (1996) The aetiology and management
of erectile, ejaculatory and fertility problems in men with diabetes
mellitus. Diabet Med 13(8): 700-708.
Conclusion
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Citation: Garber MG and Carlos ND (2015) Intracavernous Administration of Adipose Stem Cells: A New Technique of Treating Erectile Dysfunction
in Diabetic Patient, Preliminary Report of 6 Cases. MOJ Cell Sci Rep 2(1): 00018. DOI: 10.15406/mojcsr.2015.02.00018